This application is for a Program Project Grant to evaluate both basic mechanisms and possible new treatments for acute long injury. High concentrations of oxygen and septic lung injury are th primary models that will be evaluated. The complex relationships between the therapeutic effects of hyperoxia, oxidative damage produced y reactive oxygen species both in the lung and in peripheral tissues, physiologic regulation of tissue oxygen concentrations in response to hypoxia, and the role of extracellular antioxidants and adhesion molecules in modulating lung inflammatory reactions re the primary focus of this application. The proposal consists of four projects and three core units. Project 1 will evaluate the mechanisms and treatment of hyperoxic lung injury. Aerosolized therapy with extracellular antioxidant enzymes will be optimized and new superoxide dismutase mimetics will be developed and tested. Project 2 will evaluate oxidative stress and the regulation of oxygen metabolism in peripheral tissues during acute long injury and will assess whether or not septic lung injury can be effectively treatment using extracellular antioxidants or monoclonal antibodies to leukocyte adhesion molecules. Project 3 will evaluate the regulation of the synthesis of extracellular antioxidant enzymes under various conditions of oxidant stress. Project 4 will use immunocytochemistry and cell biology to define the role of intercellular adhesion molecules in modulating information in alveolar air spaces and in the lung interstitium. The overall rationale for the Program Project is to use an interdisciplinary approach to define the cellular pathways involved in oxidant mediated lung and tissue injury and to define new approaches for pharmacologic therapy that can be readily translated to a large primate model and following that to the treatment of humans with ARDS and sepsis.